Central cannabinoid receptors (CB1) have gained interest as a therapeutic target. Agonist activated CB1 receptors propagate their signals downstream via coupling with G-proteins. Normally, this coupling occurs at a high efficiency, resulting in a high receptor reserve. Both aging and ethanol exposure reduce the efficiency of cannabinoid receptor coupling with G-proteins, and thus receptor reserve. Similarly, inbred C57BL/6J mice have higher cannabinoid receptor reserve than inbred DBA/2J mice, suggesting strain- dependent responses to cannabinoids. However, the impact of differences in cannabinoid receptor reserve on behavioral responses to cannabinoids remains unclear. The present proposal is designed to examine the effects of the CB1 agonist delta-9-tetrahydrocannabinol (THC) and the CB1 inverse agonist/partial agonist rimonabant (SR141716A) on fixed-ratio responding in rats and mice. Proposed experiments will characterize changes in the behavioral response to these drugs (alone and in combination) due to aging, ethanol exposure, or genotype. Young rats, ethanol-naive rats, and C57BL/6J mice have more efficient cannabinoid systems, resulting in higher receptor reserve. The potency of THC is expected to be enhanced in subjects with higher cannabinoid receptor reserve. Further, in subjects with a higher receptor reserve, rimonabant alone is expected to reduce response rate due to its intrinsic activity at CB1 receptors, and will be unable to completely antagonize THC effects due to this activity. Conversely, in older rats, ethanol- exposed rats, and DBA/2J mice, presumed to have a lower receptor reserve, rimonabant is expected to have no activity when administered alone and should completely antagonize THC effects. In addition to fostering the development of the applicant into an independent researcher, the present proposal will characterize the behavioral pharmacology of cannabinoids under conditions known to alter cannabinoid system efficiency. These studies will provide valuable information linking cellular and behavioral effects of cannabinoids. LAY SUMMARY: Cannabis is thought to produce euphoric and therapeutic effects through the cannabinoid receptors in the brain. Drugs that act at these receptors are important because they are involved in cannabis abuse and may be valuable medications. This project will help us understand how aging, exposure to ethanol, and perhaps genetic disposition change the behavioral response to these drugs. [unreadable] [unreadable] [unreadable]